L34B - Drug Distribution 1

Question 1

What is drug distribution?

Answer 1

The reversible transfer of drug from on site to another within the body

Question 2

What are facts about blood circulation enables efficient drug distribution? (4) (numbers not asked)

Answer 2

• avg subject has 5L of blood = 3L plasma
• avg cardiac output is 5.5L/min at rest
• mixing of drug solution in the blood occurs very fast
• tissue distribution takes time, rate and extent depending on drug and tissues

Question 3

What is cardiac output?

Answer 3

Amount of blood the heart pumps through the circulatory system in a minute

Question 4

What is tissue differences in drug sitribution and blood circulation?

Answer 4

Some tissues haev more drug flow, so potentially more exposure to drugs

Question 5

What are the distribution (potential) steps? (2)

Answer 5

• passage of capillary membrane
• passage of cell membrane

Question 6

What is paracellular movement of drug influenced by?

Answer 6

Tighetness of the intercellular junctions

Question 7

What are the 2 categories of transcellular pathways?

Answer 7

• those involving simple diffusion
• those involving facilitative mechs like transporters

Question 8

What does movemenr of drugs across membrane occur through?

Answer 8

Paracellular ans transcellular pathways

Question 9

What are the distribution processes? (3)

Answer 9

• passive diffusion
• transporters
• hydrostatic pressure

Question 10

What is hydrostatic pressure like?

Answer 10

• arterial end pressure > tissue pressue
• tissue pressure > venous pressure

Question 11

What is the movement like from capillaires to intersitial fluid (ISF)? (3)

Answer 11

• drug transport is independent of lipophilicity, charge and molecular size
• usually easy paracellular transport
• larger molecules, charge becomes more important (-ve = lower perm across renal glomerulus)

Question 12

What is the movement like from interstitial fluid (ISF) to cells?

Answer 12

passage across is very dependent on:
- drug physicochemical properties (size, charge, lipophilicity)
- drug being subtrate for influx/efflux transporters

Question 13

What is drug transport across blood-brain barrier, hepatocyte and renal tubule highly dependent on? (3)

Answer 13

• lipophilicity
• charge
• molecular size

Question 14

What are the effects of charge like?

Answer 14

• large
• exceptions = paracellular transport across the blood capillary membranes and renal glomerulus)

Question 15

What is membrane transport like for charged drugs?

Answer 15

Membrane transport is slower
- degree of ionisation at physiological pH determines movement across membranes

Question 16

What is the pH partitiom hypothesis like?

Answer 16

• assumues only un-ionised drug penetrates membranes
• at eq, conc of unionised species are equal on both sides
• at eq, conc of ionised species is larger at the side with lower pH for a WB
• at eq, total conc is larger at side with lower pH

Question 17

What is the pH in the body?

Answer 17

• gastric 1.5-7.0
• intestinal 6.2-7.5
• urine 5.0-7.5
• Elsewhere ~ pH of blooe (7.4)
• excp. Acidic intracellular lysosomal region (pH 5)

Question 18

What are transporters like from blood to tissues, into cells and back?

Answer 18

• eq transporters vs active transporters/conc transporters
• efflux vs influx/uptake
• acpical side vs basolateral

Question 19

What do transporters play an important role in?

Answer 19

• distribution of some drugs
• absorption and elimantion of some drugs
• therapy success - resistance of tumour cells to some drugs, acess to target site

Question 20

What are transporters as part of the brain blood barrier like from blood to tissues, into cells and back?

Answer 20

• passage is highly dependent on lipophilicity, charge and molecular size
• permeability increases progessively with increasgin lipophilicity (not always)
• vinblastine and vincristine have permeability lower than expected, due to efflux PGP

Question 21

What can drugs bind to?

Answer 21

• tissue components
• plasma proteins
• RBCs

Question 22

What is the binding eq in plasma like?

Answer 22

• very fast
• usually reversible
• dif drugs bind to dif plasma proteins (acidic drugs to albumin, basic drugs to a1-acid glycoprotein, neutral compounds to lipoproteins)

Question 23

What can bound drugs not do?

Answer 23

Diffuse across biological membranes - cannot cross capillary membranes

Question 24

What is plasma binding a key determinant of?

Answer 24

Drug distribution

Question 25

What is the degree of binding for a drug expressed as?

Answer 25

Bound fraction (fbound)
Fbound = [drug]bound/[drug]total

Question 26

What is free conc of a drug in plasma?

Answer 26

Cfree = Ctotal x Fu

Question 27

How does drug binding modify drug distribution? (3)

Answer 27

• complex [drug-protein] too large to diffuse across membrane
• only free drug is able to distribute out of plasma
• drug distribution is V dependent on the drugs binding affinity to BOTH plasma and tissue components

Question 28

What are the different ways drug can binf to tissues? (3)

Answer 28

• drug neither bind to plasma proteins nor tissues
• drugs binds to plasma proteins but not to tissues
• drug binds to tissue components but not to plasma proteins

Question 29

What is affininty for a tissue better described by as for some drugs?

Answer 29

Partitioning phenomena rather than binding process

Question 30

How can you descrube the affinity through a partition coefficient?

Answer 30

Ptissue/blood = Cdrug,tissue/Cdrug,plasma